N-(4-carboxyphenyl)anthranilic acid



United States Patent 3,511,873 N-(4-CARBOXYPHENYL)ANTHRANILIC ACIDGiampaolo Picciola, Milan, Italy, assignor to Italfarmaco S.p.A., Milan,Italy, a corporation of Italy No Drawing. Filed Oct. 18, 1966, Ser. No.587,437 Claims priority, application Italy, Sept. 3, 1966, 20,206/ 66Int. Cl. C07c 101/48 US. Cl. 260-471 Claims ABSTRACT OF THE DISCLOSURECompounds having anti-pyretic, anti-inflammatory and analgesic activityhaving the structural formula:

COOX

wherein X is hydrogen or an alkaline or earth-alkaline metal cation or acation of a non-toxic organic base and Y is hydrogen or lower alkyl.

COOX

@NHQOOOY wherein X represents hydrogen or an alkaline or earthalkalinemetal cation or a cation of non-toxic organic base, particularly the [3hydroxy ethyl dimethylammonium cation, while Y represents hydrogen or alower alkyl radical having 1 to 4 carbon atoms in a linear or branchedchain, and a process for their preparation.

According to the invention, the compounds of general Formula I, whereinY is difierent from hydrogen, are prepared by condensation ofo-bromo-benzoic acid, under the form of a sodium or potassium salt, withan aromatic amine bearing in 4-position, a substituent of formula COOY,wherein Y represents an alkyl group having 1 to 4 carbon atoms in linearor branched chain, in the presence of a Cu-containing catalyst and of apro ton acceptor, in a suitable solvent, at a temperature between 75 and150 C. N-(4-carboxyphenyl)anthranilic acid can be obtained by hydrolysisof any of its corre sponding esters.

In the preparation of the substances which are the subject of thisinvention, the o-bromobenzoic acid salt employed can be preparedseparately, or directly in the reaction solvent, by neutralizing theacid with an alkaline carbonate, as for example, that of potassium andby distilling out the water formed.

The copper utilized as a catalyst in the condensation can be employed asa mechanically or chemically obtained powder, or as cuprous or cupricsalts, as bromide or acetate. The solvent can be amyl, iso-amyl alcoholand higher alcohols, or the same proton acceptor if it is constituted byan organic base. The proton acceptor can be an alkaline metal carbonate,such as potassium carbonate, or a tertiary amine such asN-ethylmorpholine, or an aromatic amine bearing in 4-position asubstituent of formula COOY, wherein Y represents an alkyl group having1 to 4 carbon atoms in a linear or a branched chain.

The compounds according to the invention show an anti-pyretic,anti-inflammatory and analgesic activity and 3,511,873 Patented May 12,1970 EXAMPLE 1 N- (4-carboethoxyphenyl) anthranilic acid In a 4-necked500 ml. reactor, there are placed 15 g. potassium o-bromo-benzoate (mol.wt. 239.13) (0.0627 mole), 20.76 g. ethyl p aminobenzoate (mol. wt.165.19) (0.1255 mole), 0.400 g. copper acetate, and 150 cc. amylalcohol. The mixture is refluxed for four (4) hours. Then it is cooled,ml. water is added, then the amyl alcohol is steam distilled. Theresidual mixture is. cooled, the copper salts are filtered 01f, thefiltrate is acidified with hydrochloric acid, extracted with ether, theethereal extract is dehydrated and evaporated to dryness. The residue isa solid, which is recrystallized from benzene. The product obtained is5.65 g. (yield 31.5%); M.P. 175.5176.5 C. The product has been titratedpotentiometrically in ethanol-water (1.5 :1). The 1% solution inabsolute ethanol shows:

Max. at 225 m =670 Min. at 265 m .=37

Max at 344-345 mu=830 Flex. at 332 ElIl/L EXAMPLE 2N-(4-carbobutoxyphenyl)anthranilic acid In a 4-necked 500 ml. reactorthere are placed 15 g. potassium o-bromobenzoate (mol. wt. 239.13)(0.627 mole), 24.259 g. butyl p-aaninobenzoate (-mol. wt. 193.24)(0.1255 mole), 0.400 g. copper acetate and ml. amyl alcohol. The mixtureis refluxed for 4 hours; then it is cooled, 100 ml. water are added, theamyl alcohol is steam-distilled off. The residual mixture is cooled, thecopper salts filtered ofl, the filtrate is acidified with hydrochloricacid, extracted with ether, the ethereal extract is dehydrated andevaporated to dryness. The residue is an oil, which is crystallized fromligroin. The product obtained is 6.75 g. (yield 34.35%); M.P. 119.5120.5 C. The product is titrated potentiometrically with N/ 10 NaOH inethanol-water (1.5: 1). The 1% solution in absolute ethanol shows thefollowing:

Max. 225 m,u=620 Min. 265 rn =29 Max. 344 m i=770 Flex. at 322 m EXAMPLE3 N (-4 oarbo-t-butoxyphenyl) anthranilic acid In a 4-necked 500 ml.round flask there are added 18.21 g. o-bromobenzoic acid (mol. wt.201.03) (0.0906 mole), 6.3 g. K CO (mol. wt. 138.192) (0.0453 mole), and150 ml. amyl alcohol. The mixture is refluxed for 1 hour and 30 minutes.The H O formed is distilled off; the reaction mixture is cooled, andthere are added 17.5 g, t.butyl ester of p-aminobenzoic acid (mol. Wt.193.24) (0.0906 mole) prepared according to Adams, Am. Soc. 48, 1768-69;12.66 g. ethyl morpholine (mol. wt. 115.18) (0.11 mole), 0.800 g. 011acetate and 50 ml.

amyl alcohol. The mixture is refluxed for 4 hours. Then there is added100 ml. H 0 and the amyl alcohol is steam-distilled. The reactionmixture is filtered, acidified with HCl, extracted With ether, theethereal extract is evaporated to dryness. The residue isre-crystallized from ligroin. Melting point 164.5165.5 C. Yield 30%. Theproduct is titrated with NaOH in ethanol-H O (1:1).

EXAMPLE 4 N-(4-carboxyphenyl)anthranilic acid COOH l NHC 0 on 11101. wt.257.236

N-(4-carboxyphenyl) antfinranilic acid is prepared by hydrolyzing thecorresponding (in 4-positi0n) esters. For example:

In a 500 ml. round flask there is added 20 g. N-(4-carbobutoxyphenyhanthranilic acid (mol. wt. 313.3419) (0.06382 mole),15 ml. ethanol, 7.895 g. 97% NaOH pellets (mol. Wt. 40) (0.19146 mole)and 100 ml. H O.

The mixture is refluxed for three hours, then it is diluted with 300 ml.H O, filtered with charcoal, acidified wherein X is a member selectedfrom the group consisting of hydrogen, an alkaline metal cation, anearth-alkaline metal cation, and a cation of a non-toxic organic base,and Y is a member selected from the group consisting of hydrogen and analkyl radical having 1 to 4 carbon atoms.

2. 'N- (4-carboxyphenyl) -anthranilic acid.

3. N-(4-carboethoxyphenyl) -anthranilic acid.

4. N- (4-carbo-n-butoxyphenyl) -anthranilic acid.

5. N-(4-carbo-t-butoxyphenyl)-anthranilic acid.

References Cited UNITED STATES PATENTS 3,369,042 2/1968 Scherrer 260-471LORRAINE A. WEINBERGER, Primary Examiner L. A. THAXTON, AssistantExaminer US. Cl. X.R.

